Efficacy of pimecrolimus in
infants
The efficacy of pimecrolimus for the treatment of AD in infants has been
extensively evaluated in multiple vehicle-controlled pivotal trials
(Table 1 ). These trials have consistently demonstrated that
topical pimecrolimus treatment results in effective long-term control of
AD in infants (46-50). Twice-daily application of pimecrolimus in
infants effectively reduced the risk for flares compared with vehicle,
with 67.6% versus 30.4% of patients completing 6 months without flares
(P <.001), resulting in an absolute risk reduction of
37.2%, which was independent of baseline severity (47). Additionally,
the mean Eczema Area and Severity Index (EASI) was already reduced by
approximately 70 – 80% after 4 weeks of pimecrolimus treatment, while
there was no symptom relief at this timepoint for infants who were
treated with vehicle control (46, 50). Furthermore, this response was
irrespective of disease severity and significant even for infants with
very severe disease (Investigator’s Global Assessment [IGA] ≥4)
(46). The earliest significant reduction in EASI was reported from day 4
onwards, with a reduction of 38.5% and 17.6% after 4 days of
pimecrolimus and vehicle treatment, respectively
(P <.001) (46). Importantly, the early and sustained
treatment success (IGA 0 or 1) observed in the head and neck area was
similar to that of the whole body. A rapid response in sensitive skin
areas is especially important in infants who mostly have a sensitive
skin structure to decrease the disease burden as early as possible (46).
Furthermore, disease control with pimecrolimus was proven to be
long-term, with approximately 70% of patients having minimal or no
disease, as assessed by the IGA score and EASI, after 2 years of
intermittent pimecrolimus treatment (48). Similar to the reductions seen
in EASI and IGA scores, pimecrolimus effectively relieved pruritus,
which was associated with significant improvements in the QoL and sleep
behavior of the infant. Already within the first week of use, 70% of
infant patients reported absence of mild pruritus compared to about half
of the patients treated with vehicle (46-48, 50-52). Also, parents
experienced significant improvements in psychosomatic well-being, social
life, confidence in medical treatment, and emotional coping after 4
weeks of treatment of their infants (51). These improvements in QoL of
parents were found to be sustained up to 1 year of treatment and
probably thereafter, as they coincided with long-term disease control of
their infants (52). Although not evaluated in this study, such impact on
QoL presumably also decreases the substantial economic burden of the
disease. In the vehicle-controlled trials, use of pimecrolimus was found
to decrease over the course of long-term treatment upon clearance of
symptoms, but importantly discontinuation was not associated with
rebound flares, as has been described for TCS (46, 48, 53). Pimecrolimus
treatment also had a steroid-sparing effect in the infant, which was
reflected by a decrease in overall use and an increased time to first
use of TCS as well as a reduced number of days on TCS therapy (47, 49).
Head-to-head comparisons between pimecrolimus and tacrolimus in the
pediatric population were assessed in two RCTs, which evaluated both
treatments in children of 2 to 17 years of age (54, 55). These two
trials were also included in a meta-analysis, demonstrating that
pimecrolimus and tacrolimus have comparable efficacy in children with AD
(56). However, to the best of our knowledge, there is only one 24-month
open-label phase II clinical trial evaluating safety and efficacy of
tacrolimus in 50 infants below the age of 2 years, indicating additional
studies are needed to evaluate tacrolimus for the infant indication
(57).
To support the use of pimecrolimus as an alternative treatment to TCS in
infants, the PETITE study was designed to compare the long-term safety
and efficacy of TCS and pimecrolimus for the treatment of infants with
AD in a real-world setting (58). In total, 2,418 infants aged between 3
and 12 months were randomized to receive either pimecrolimus (n=1,205)
or mild-to-moderate potency TCS (n=1,213) (58). However, short-term use
of TCS was allowed in case disease flares could not be controlled by
pimecrolimus treatment. The PETITE study confirmed the previous results
from the vehicle-controlled trials, showing that pimecrolimus relieved
symptoms in more than 50% of patients already after 3 weeks of
treatment. The onset of disease control was comparable between
pimecrolimus and TCS, and treatment with both anti-inflammatory drugs
resulted in almost complete clearance of symptoms in more than 85% of
patients after 1.5 years of intermittent treatment. Accordingly, less
than 5% of body surface area was affected in week 3, with no eczematous
lesions after 1.5 year of treatment in both groups which was maintained
until the end of the study (58). Importantly, pimecrolimus was
steroid-sparing, as 36% of patients in the pimecrolimus group did not
use any TCS during the 5 years follow-up period (58). Whether or not the
reduced need for TCS improves treatment adherence by overcoming concerns
related to corticophobia remains to be formally demonstrated. However,
it is well-established that use of TCS is causing epidermal thinning and
skin atrophy, while pimecrolimus can restore certain aspects of the
epidermal barrier (22). As infants overall have a sensitive structure of
the skin, this is an additional factor favoring long-term use of
pimecrolimus over TCS for infants with AD.
So far, the Study of the Atopic March (SAM) is the only RCT that
examined the impact of pimecrolimus versus vehicle treatment on the
development of atopic comorbidities in infants with AD (30, 33). This
initial study found no effect of early pimecrolimus treatment on the
development of atopic comorbidities which may be at least partially
attributed to the unexpectedly high discontinuation rate (48%) due the
fact that the trial was conducted just after implementation of the
black-box warning for pimecrolimus (30, 33). Nevertheless, rates of food
allergies, asthma, and allergic rhinitis were all lower than previously
reported, not excluding an effect of early treatment (30). Additionally,
most infants were not presenting with severe disease and rescue therapy
with TCS was permitted in both treatment groups, which may have
compromised the results (30). Due to the aforementioned limitations, it
remains currently unclear whether early intervention with pimecrolimus
for treatment of AD in infants may prevent the development of atopic
comorbidities.